{"doi":"10.4049/jimmunol.2200208","title":"Tolerogenic Immune-Modifying Nanoparticles Encapsulating Multiple Recombinant Pancreatic β Cell Proteins Prevent Onset and Progression of Type 1 Diabetes in Nonobese Diabetic Mice","abstract":"Abstract Type 1 diabetes (T1D) is an autoimmune disease characterized by T and B cell responses to proteins expressed by insulin-producing pancreatic β cells, inflammatory lesions within islets (insulitis), and β cell loss. We previously showed that Ag-specific tolerance targeting single β cell protein epitopes is effective in preventing T1D induced by transfer of monospecific diabetogenic CD4 and CD8 transgenic T cells to NOD.scid mice. However, tolerance induction to individual diabetogenic proteins, for example, GAD65 (glutamic acid decarboxylase 65) or insulin, has failed to ameliorate T1D both in wild-type NOD mice and in the clinic. Initiation and progression of T1D is likely due to activation of T cells specific for multiple diabetogenic epitopes. To test this hypothesis, recombinant insulin, GAD65, and chromogranin A proteins were encapsulated within poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles (COUR CNPs) to assess regulatory T cell induction, inhibition of Ag-specific T cell responses, and blockade of T1D induction/progression in NOD mice. Whereas treatment of NOD mice with CNPs containing a single protein inhibited the corresponding Ag-specific T cell response, inhibition of overt T1D development only occurred when all three diabetogenic proteins were included within the CNPs (CNP-T1D). Blockade of T1D following CNP-T1D tolerization was characterized by regulatory T cell induction and a significant decrease in both peri-insulitis and immune cell infiltration into pancreatic islets. As we have recently published that CNP treatment is both safe and induced Ag-specific tolerance in a phase 1/2a celiac disease clinical trial, Ag-specific tolerance induced by nanoparticles encapsulating multiple diabetogenic proteins is a promising approach to T1D treatment.","journal":"The Journal of Immunology","year":2022,"id":243329,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":34,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.954,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":418078,"name":"Samantha Genardi","orcid":"0000-0003-3133-5236","position":1,"is_corresponding":false},{"id":582867,"name":"Ming‐Yi Chiang","orcid":null,"position":2,"is_corresponding":false},{"id":875104,"name":"Sandeep Kakade","orcid":"0000-0001-6619-0386","position":3,"is_corresponding":false},{"id":741876,"name":"Tobias Neef","orcid":"0000-0002-8256-1455","position":4,"is_corresponding":false},{"id":875706,"name":"Tushar Murthy","orcid":null,"position":5,"is_corresponding":false},{"id":875707,"name":"Michael T. Boyne","orcid":null,"position":6,"is_corresponding":false},{"id":625496,"name":"Adam Elhofy","orcid":"0000-0002-3060-7829","position":7,"is_corresponding":false},{"id":242015,"name":"Stephen D. Miller","orcid":"0000-0002-9556-0718","position":8,"is_corresponding":false},{"id":260784,"name":"Joseph R. Podojil","orcid":"0000-0002-5818-8515","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T00:23:16.032700Z","pmid":"35725270","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}